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6 Pervasive Developmental Disorders (PDD)/Autism Spectrum Disorder (Autism)

6 Pervasive Developmental Disorders (PDD)/Autism Spectrum Disorder (Autism)

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PERVASIVE DEVELOPMENTAL DISORDERS (PDD)/AUTISM SPECTRUM DISORDER (AUTISM)



121



development, including speech followed by severe regression between ages 2 and 10

years affecting language, social skills, cognition, and daily life skills), Asperger syndrome, Rett syndrome, and PDD not otherwise specified (children are less severely

affected and do not meet classifications of classic autism or Asperger syndrome).

Autism disorder is among the most common developmental disorders. Estimates

of the prevalence of all autism spectrum disorders has been estimated as high as

10–60 in 10,000, with males being more commonly affected than females (Rutter

and Simonoff, 2007; Sikich et al., 2006). The diagnosis is usually made in the first

3 years of life, though development in the 1st year may appear normal (Rutter and

Simonoff, 2007). Characteristic features include impairments in processing social

and environmental information, language abnormalities (30% have no speech), and

repetitive or stereotyped behaviors. Severe intellectual disability (IQ below 70) is

seen in about 75% of autistic individuals. Persons with Asperger syndrome may have

normal intelligence or be considered gifted. Strengths are usually in visuospatial

skills, with larger deficits in verbal, abstraction, and conceptualization skills (Rutter

and Simonoff, 2007). Other features associated with PDD/autism include a head

circumference above that of the 98th percentile (macrocephaly, which may occur

postnatally), epilepsy (affecting about 25%), a history of minor obstetric complications (unexplained by environmental risk factors), and minor congenital anomalies

particularly involving the external ear. Environmental agents such as rubella are also

a cause. (Schaefer and Mendelsohn, 2008).

Autism has a heterogeneous etiology. A genetic etiology has been identified in

6–15% of persons with autistic-like features, suggesting that all patients with autisticlike features would benefit from a genetic evaluation (Abdul-Rahman and Hudgins,

2006, Shaefer and Mendelsohn 2008). Autistic features seem to be a marker for

abnormal brain development, and the current classification of the pervasive developmental disorders seems most useful for treatment and less important in determining

etiology. In determining a genetic etiology of autism, it is important to first confirm

the diagnosis of autism. Hearing loss can be mistakenly diagnosed for autism (Shaefer

and Mendelsohn, 2008).

Chromosomal analysis with high-resolution prometaphase karyotype (band level

greater than 550) produces the greatest yield, particularly if the individual has any

minor physical anomalies. FISH analysis is recommended for 22q11.2 deletion (velocardiofacial/DiGeorge syndrome) and 15q duplication (the Prader-Willi/Angelman

syndrome critical region) or deletion. In fact, 15q aberrations may be among the most

common cause of autism. Use of subtelomeric FISH analysis or aCGH (microarraybased comparative genome hybridization) for people with autism is still being evaluated for efficacy of detecting anomalies, but given the relatively low cost and the

ability to test for a variety of putative loci for autism, aCGH is likely to become a

standard part of an autism evaluation (Schaefer and Mendelsohn, 2008).

To date, the most common single-gene disorders associated with autistic-like

features include:

r Rett syndrome, an X-linked condition with lethality in males, is associated with

mutations in MECP2. This diagnosis should be considered in females with



122



r

r



r



r



r



DIRECTED MEDICAL-GENETICS FAMILY HISTORY QUESTIONS



developmental delay who are identified before age 4 years, particularly if there

is normal early development followed by global regression, developing microcephaly, and loss of purposive hand movements with characteristic “midline hand washing.” Limited studies suggest that 3–13% of female children

with autistic features and developmental delay will have an MECP2 sequence

mutation. (Schaefer and Mendelsohn, 2008). Mutation in MECP2 is not universally lethal in males and is a cause of autism and developmental delay in

males.

Fragile X syndrome, an X-linked disorder, affects less than 3% of persons with

autism.

Tuberous sclerosis complex, an autosomal dominant condition, affects an estimated 3–4% of individuals with autism (Rutter and Simonoff, 2007). Approximately 25% of persons with tuberous sclerosis complex have autism.

Persons with macrocephaly (a head circumference greater than 2.5 standard

deviations above the mean) and autism spectrum disorder should have PTEN

genetic analysis even without additional clinical or family history features suggesting Cowden syndrome (Buxbaum et al., 2007; Herman et al., 2007; Orrico

et al., 2008).

Virtually 100% of persons with Smith-Lemli-Opitz syndrome have autism. Studies testing for 7-dehydro-cholesterol levels in persons with idiopathic autism

have not been done, but this may become part of the screening protocol for

autism (Sikora et al., 2006).

For people with an X-linked pattern of neurobehavioral and nerurodevelopmental disorders and cognitive defects, genetic testing for neuroligin3 (NGN3)

and neuroligin 4 (NGN4) are a consideration (Schaefer and Mendelsohn,

2008).



Autistic disorder is considered to have a polygenic/multifactorial etiology. The

chance that parents of a child with autism will have another affected child is 3–6%

(unless a genetic syndrome is identified) (Sikich et al., 2006), with the risks to

second- and third-degree relatives being in the range of 0.13% and 0.05%, respectively (Jorde et al., 1991). The recurrence risk increases to up 50% with a

second affected child (Schaefer and Mendelsohn, 2008). The siblings of an individual with autism are also at slightly increased risk to have behavioral problems

as well as subtle deficits in speech, language, and social functioning (Rutter and

Simonoff, 2007). The medical-family history questions related to autism are reviewed

in Table 4.14.



4.7 CEREBRAL PALSY

Cerebral palsy is a heterogenous collection of clinical conditions that describe a

nonprogressive physical disorder that affects movement and posture (Raymond,



CEREBRAL PALSY



TABLE 4.14



123



Medical-Family History Questions for Autism



r Were there any complications with the pregnancy or birth of the child?

r Did the mother take any medications, alcohol, or street drugs in the pregnancy? (specifically

r

r

r

r

r

r



r



alcohol exposure, valproic acid)

Did the mother have any illness in the pregnancy? (rubella, cytomegalovirus)

At what age were the problems with language/socialization/behavior noted?

Do you know the individual’s IQ? (obtain records)

Has normal hearing been confirmed?

Are there any food intolerances?

Has there been regression/loss of skills? (Consider MECP2 in females; metabolic screening

such as urine mucopolysaccharides and organic acids, serum lactate, amino acids,

ammonia, and acyl-carnitine profile, depending on what has already been tested for in the

newborn screening panel.)

What type of diagnostic testing has been done? (obtain any reports)



r Has the individual had a routine karyotype and/or fragile X (FMR1) DNA studies? (confirm

band-level of karyotype)



r Have comparative genomic hybridization (aCGH) studies been done?

r What conditions were screened for in the newborn screening test?

r Have neuroimaging studies been done? (particularly in instances of macrocephaly,

microcephaly, and seizure disorder)



r Does the individual or any relatives have:

r A large head (2.5 standard deviations greater than the mean)? (consider FMR1, PTEN )

r Small head? (fetal rubella, Smith-Lemli-Opitz, many chromosomal syndromes;

r

r

r

r



deceleration in head growth seen in Rett syndrome)

Any unusual facial characteristics?

Any minor physical anomalies?

A history of seizures? (obtain EEG)

Any unusual birthmarks or skin problems? (ashleaf-hypopigmented spots, Shagreen

patch, adenoma seabaceum, angiofibromas, and periungual fibromas in tuberous

sclerosis complex; trichelemmomas, acral keratoses, lipomas, and papillomatous papules

in Cowden syndrome; large areas of hypopigmented streaks or whorls along the lines of

Blaschko in hypomelanosis of Ito)

Any other medical problems?



r

r Is there a family history of:

r Miscarriages?

r Cognitive delay (mental retardation), learning disabilities, or autism?

r Behavioral problems?

r Seizures?

r Cancer? (particularly thyroid, breast, uterine, or kidney cancer as seen in Cowden

syndrome)



r Are the parents related as blood relatives?

Sources: Abudul-Rahman and Hudgins, 2006; Rutter and Simonoff, 2007; Schaefer and Mendelsohn, 2008.



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DIRECTED MEDICAL-GENETICS FAMILY HISTORY QUESTIONS



2007). There is no on-going pathological process, though the clinical features

can change with age and brain maturity (Firth and Hurst, 2005). The main classifications of cerebral palsy (Firth and Hurst, 2005; Wilson and Cooley, 2006)

include:

r Spastic cerebral palsy (decreased muscle strength with increased muscle tone and

brisk reflexes)

r Spastic hemiplegia (nonsymmetrical)

r Spastic diplegia (symmetrical with the legs affected more than the arms; there is

a higher incidence of intellectual disability)

r Spastic quadriplegia or tetraplegia (all four limbs are affected)

r Athetoid cerebral palsy (characterized by involuntary movements and loss of control of posture; includes dyskinetic, dystonic, extrapyramidal, choreathetoid)

r Ataxic cerebral palsy (generally reflects cerebellar involvement with poor coordination of movements and wide-based gait, tremor may be observed)

r Atonic or hypotonic cerebral palsy (hypotonia, decreased muscle tone beyond the

1st year of life)

Cerebral palsy is a common disorder with a prevalence of approximately 1.5 to

2.5 in 1,000 births (depending on how cerebral palsy is defined) (Raymond, 2007).

The spastic forms are the most common. Cerebral palsy is rarely inherited (Firth

and Hurst, 2005; Raymond, 2007). Despite popular beliefs, birth trauma is not a

frequent cause of cerebral palsy (<5%) (Raymond, 2007). The etiology of cerebral

palsy cannot be determined for many persons with cerebral palsy; the most common

associations include (Firth and Hurst, 2005; Raymond, 2007; Wilson and Cooley,

2006):

r Prematurity

r Low birth weight (<1,500 g) (confers a 25–30 times increased risk of cerebral

palsy)

r Infections (prenatal and postnatal)

r Bleeding in the first trimester (e.g., vascular event, loss of a twin)

r Twin gestation

r Cerebral dysgenesis (alterations in the formation of the central nervous system

such as abnormal migration or proliferation leading to congenital malformation

in the size, structure, and function of the brain—for example, lissencephaly,

agenesis of the corpus callosum)

r Anoxia

There are several genetic conditions that may be misdiagnosed as cerebral palsy,

or in which features of cerebral palsy are seen; most of these conditions are neurodegenerative and have other clinical symptoms that aid in diagnosis. Rare inherited



NEUROLOGICAL AND NEUROMUSCULAR DISORDERS



125



conditions to consider (Firth and Hurst, 2005; Raymond, 2007; Wilson and Cooley,

2006) include:

r Mitochondrial disorders

r Inborn errors of metabolism:

r Arginase deficiency (AR)

r Abetalipoproteinemia (AR)

r Fatty aldehyde dehydrogenase deciency (Sjăogren-Larsson syndrome)

r Ornithine translocase deciency or hyperornithemia-hyperammnomeiahomocitullinuria

r Pyruvate dehydrogenase deficiency

r Perioxisomal disorders

r Zellweger spectrum

r Dopa-responsive dystonia (most are autosomal dominant with mutations in DYT5)

r Rett syndrome due to MECP2 mutations (X-linked)

r Angelman syndrome (imprinting defect)

r X-linked intellectual disability due to ARX mutations

r Biallelic factor V mutations (perinatal stroke)

r Leukodystrophies:

r Metachromatic leukodystrophy (AR)

r Krabbe disease (AR)

r Adrenoluekodystrophy (X-linked)

r Movement disorders:

r Wilson disease (AR)

r Ataxia telangiectasia, (AR)

r Lesch-Nyhan syndrome (X-linked)

Suggested medical-family history questions for cerebral palsy are given in Table

4.15. Even if an etiology for cerebral palsy is not determined, it is often comforting

to parents to point out that they did not cause their child’s problems because this

is a common belief. This is another condition where it is particularly important to

hear the parents’ and family’s beliefs about causality of the problem (such as birth

trauma), and then respectfully provide some more likely explanations.



4.8 NEUROLOGICAL AND NEUROMUSCULAR DISORDERS

Molecular diagnosis is creating an upheaval in the classification systems of genetic

neurological diseases. The spinocerebellar ataxias (SCA) are now classified into

more than 30 subtypes, depending on the molecular etiology; some types have been

described in only one family. The nomenclature flip-flops back and forth between

the hereditary motor sensory neuropathies (HMSN) and the subtypes of CharcotMarie-Tooth (CMT) as molecular diagnosis refines the phenotypes. Many of the

forms of muscular dystrophy can now be distinguished by molecular testing. Not



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DIRECTED MEDICAL-GENETICS FAMILY HISTORY QUESTIONS



TABLE 4.15



Medical-Family History Questions for Cerebral Palsy



Pregnancy history for the mother of the child/person with cerebral palsy:

r Was there anything unusual about the pregnancy? (e.g., infections, bleeding loss of a twin,

lack of fetal movement)

r Did the mother have any illnesses in pregnancy? Describe nature of illness, diagnostic

evaluation, treatment, timing in pregnancy.

Birth history of the person with cerebral palsy:

r Was the child born prematurely?

r What was the birth weight?

r Do you know the Apgar scores?

r Was the child admitted to the neonatal intensive care unit? Obtain details

For the person with cerebral palsy:

r Is the head circumference normal? (Ideally obtain growth charts and charts of growth of

head circumference.)

r What evaluations have been done?

r Brain imaging? (MRI can identify any lesions compatible with asphyxia, prematurity,

congenital stroke, structural brain anomalies, basal ganglia lesions, agenesis of the

corpus callosum, and lissencephaly.)

r Karyotype and/or array CGH?

r Any abnormalities on newborn screening? (particularly for amnio acid and organic acid

disorders)

r Is there progression (worsening) of symptoms?

r Does the person with cerebral palsy look like other relatives? Is there anything unusual about

the way the person looks? (If so, consider syndromic conditions, karyotype and/or array

CGH.)

Does the person with cerebral palsy and/or his or her relatives have a history of:

r Intellectual impairment?

r Seizures?

r A movement disorder?

r Ataxia?

r Unusual birth marks or skin disorder?

r Congenital anomalies?

Are the parents of the child/person with cerebral palsy related as cousins or more closely

related? (suggests autosomal recessive inheritance)

Sources: Firth and Hurst, 2005; Raymond, 2007; Wilson and Cooley, 2006.



only is this flurry of molecular advances recasting the stage of how we think about

neurological disorders but molecular genetic blood tests may also save a person from

invasive procedures such as muscle or nerve biopsies. The family-medical history

is often the first step in decision making for a diagnostic evaluation. Coupled with

the findings from the patient’s neurological exam, the medical-family history guides

the clinician in choosing from the myriad diagnostic tools available for neurological



SEIZURES



127



diagnosis. One third of single-gene defects are associated with diseases that affect the

nervous system (Gallagher, 2005). For references surveying the ever-changing field

of neurogenetics see Lynch (2006), Rosenberg et al. (2007), the Winter–Baraitser

Neurogenetics Database (http://imdatabases.com), and the disease specific reviews

in GeneReviews (www.genereviews.org) (See also Appendix A.5).

Many hereditary neurological disorders are clinically complex because the nervous system is intimately intertwined with other organ systems; therefore, the family history approach to helping identify inherited neurological conditions must be

broad. Table 4.16 outlines the medical-family history questions for a neurological

condition.

This section is followed by more specific inquiries for directed medical-family

histories for seizures, stroke dementia, and mental illness. Several hereditary conditions with neurological impairment also include hearing loss (see Section 4.3)

and/or visual impairment (see Section 4.4). Cardiomyopathies are common in the

muscular dystrophies (see Section 4.13). Inherited metabolic disorders are a frequent

inherited cause of progressive neurological conditions, particularly in children. Table

4.12 reviews some of the medical-family history indicators of an inborn error of

metabolism.



4.9 SEIZURES

Epilepsy is a group of disorders with many causes. Approximately 1% of the world

population has recurrent seizures (Prasad and Prasad, 2007). Epilepsy is a disorder

of the brain, characterized by recurrent, unprovoked, transient episodes of cortical

neuronal activity, manifesting as a motor, sensory, autonomic, cognitive, or psychic

disturbance (Prasad and Prasad, 2007). Myoclonic epilepsy is a common feature of

inborn errors of metabolism and mitochondrial disorders (characteristics of mitochondrial disorders are summarized in Table 2.5). Acquired epilepsy accounts for

one third of seizure disorders (Prasad and Prasad, 2007) and can result from any

brain injury such as head trauma, meningitis or encephalitis, asphyxia (prenatal or

postnatal), and hypoxia-ischemia from cerebrovascular disease. Seizures can also be

related to tumors and drug use.

Epilepsy may occur in isolation or as part of a syndrome (single gene, chromosomal, or mitochondrial). More than 200 inherited syndromes are associated with

seizure disorders, but they account for less than 1% of all cases of epilepsy (Prasad

and Prasad, 2007). A general epilepsy syndrome may be associated with several

different varieties of seizures. For example, generalized tonic-clinic, myoclonic, and

absence seizures may occur in juvenile myoclonic epilepsy.

The classification of seizure types is complex, and the nomenclature is changing

and is beyond the scope of this discussion. The International League against Epilepsy

has the most current updates on classifications and genetic syndromes (www.ilaeepilepsy.org). The classification is based primarily on age of onset, seizures types,



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DIRECTED MEDICAL-GENETICS FAMILY HISTORY QUESTIONS



TABLE 4.16



Medical-Family History Questions for Neurological Disordersa



r Describe the problems. Are they with strength? With sensation? With weakness? With

coordination? With intellect? With walking? With speech?



r At what age did these problems begin?

r What parts of the body are affected? For example, are there problems with weakness in

the following:

r Hands: Does the person drop things or have trouble holding a pen/pencil?

r Feet : Does the person trip frequently or have trouble lifting his or her feet such that they

make a “slapping” sound when walking? Are the feet unusually shaped? For example,

does anyone have high arches, claw or hammer toes? (common in CMT/HMSN)



r Face: Are there problems with smiling, whistling, using a straw (common in FSHMD

and MMD)?



r Arms: Does the person have trouble lifting things? Does the person have problems

combing his or her hair?



r Legs: Do you notice anything unusual about the shape of the legs? (e.g., unusually

r

r

r

r

r

r



large calves are seen in Duchenne-Becker muscular dystrophy; thin calves are seen in

the hereditary neuropathies)

At what age did the individual begin walking? (normal is between 10 and 15 months)

Was the individual ever able to run?

Did (does) he or she participate in sports? Explain.

Are the problems getting worse over time or are the stable? If worse, over what period

time? (e.g., 5 years ago, past 5 months)

Is the person able to walk on his or her own or does he or she require assistance? (e.g.,

cane, wheelchair)

Is there anything unusual about the way this person looks compared to other family

members? If yes, explain.



r Are there other neurological disorders in this individual or in other family members



such as

r Seizures? (see Section 4.9)

r Dysarthria (slurred speech)? (common in many of these disorders but particularly in

the hereditary ataxias)



r



r

r

r

r

r

r

r

r



Intellectual disability or learning disabilities? (see Section 4.5)

Problems with thinking or judgment? (note age at onset)

Problems with memory? (note age at onset)

Uncontrolled movements? (common in Huntington disease)

Gait disturbances?

Spastic movements?



Stiff movements?

Depression or mental illness (see Section 4.12)

Does this person or do other family members have a problem with alcohol abuse of

chemical dependency?



SEIZURES



TABLE 4.16



129



(Continued)



r Does the person, or other family members have other diseases or medical conditions?

Focus on

r Hearing loss? At what age? (common in NF2, several of the cerebellar ataxias,

mitochondrial myopathies, associated with some forms of HMSN/CMT; see

Section 4.3)

r Visual impairment? At what age? (visual disturbances are frequently associated with

neurological disorders, particularly retinopathies with or without mental retardation;

early onset cataracts are common in MMD; see Section 4.4)



r Skeletal anomalies, including problems with posture?

r Short stature (see Section 4.16)

r Heart disease? (particularly myopathies and cardiac conduction detects; see

Section 4.13)



r Diabetes (see Section 4.17)

r Thyroid disease

r Any unusual birthmarks or pigmentary changes? (common in tuberous sclerosis

complex, NF, cerebrotendinous xanthomastosis, and some of the rarer cerebellar

ataxias)



r Cancer? (occult carcinoma may cause symptoms of an acquired ataxia)

r What studies have been done? (e.g., nerve biopsy, muscle biopsy, nerve conduction

r



r



studies, spinal taps; imaging of the brain and/or spinal cord by MRI/ PET, or CT scans;

metabolic testing such as organic and/or amino acids, molecular testing)

What is the family’s ethnic background/country of origin? (For some neurological

conditions there is a founder effect such that certain gene alterations are easier to identify

in certain groups or the disorder may occur more frequently in individuals of certain

ancestries)

Are the parents of the individual related as cousins or more closely related?



a Abbreviations: CMT = Charcot-Marie-Tooth disease; FSHMD = fascioscapulohmeral muscular dystrophy;

HMSN = hereditary motor-sensory neuropathies; MMD = myotonic muscular dystrophy; NF = neurofibromatosis.



EEG signatures, common anatomy, and pathophysiology. The seizure types are

broadly divided into self-limited and continuous seizures and into focal (partial)

and generalized seizures.

Questions to ask for a family history of seizures are listed in Table 4.17. Seizures

are a presenting sign or an evolving feature of many of the inborn errors of metabolism

(particularly the storage disorders). Some of the common symptoms of inborn errors

of metabolism are listed in Table 4.12. It is important to obtain documentation of

any medical evaluations such as EEGs, brain imaging studies (CT, MRI, PET scans),

ophthalmologic testing, metabolic testing (plasma amino acids, urine organic acids),

and pathology reports from biopsies of skin lesions. Several anticonvulsant agents are

toxic to the fetus during pregnancy (see Table 3.2). Seizure control and the potential

teratogenic effects of medication on a developing fetus are important considerations in



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DIRECTED MEDICAL-GENETICS FAMILY HISTORY QUESTIONS



TABLE 4.17



Medical-Family History Questions for a Seizure Disordera



r Do you know the type of seizures? (e.g., focal—formerly called partial, local, focal



r

r

r

r

r

r



neocortical without local spread, clonic, myoclonic, inhibitory motor, sensory, aphasic, focal

neocortical with local spread, hippocampal and parahippocampal, generalized absence,

generalized absence myoclonic, generalized with tonic and/or clonic manifestations, atonic.)

Obtain EEG data.

Were the seizures single or repeated?

Did the seizure occur with an illness or fever?

At what age did the seizures begin? (neonatal, infancy, childhood, adolescence, as an adult)

Did the individual with seizures have any type of brain trauma or infection?

What medications does the individual with seizures take?

Did the mother of the person with seizures have any infections in pregnancy? (can be seen

in fetal toxoplasmosis, rubella, herpes, and CMV)

Does any other family member have seizures? Who?



r

r What studies have been done? (brain imaging, biochemical screening, chromosome

analysis)



Does the person with seizures or any relatives have:



r Unusual facial features? (coarsening of facial features, with ID, can be seen in storage

r



diseases—AR or XL; dysmorphic facial features, with ID, seen in several chromosome

anomalies and single-gene disorders)

Large head, protruding jaw and ears (with ID)? (characteristic of fragile X

syndrome—XL-trinucleotide repeat)

Microcephaly? (can be seen with chromosome disorders, multiple single-gene disorders)



r

r Unusual facial acne? (angiofibromas are characteristic of tuberous sclerosis

complex—TSC—AD with variable expressivity)



r Impaired hearing? (see Section 4.3)

r Problems with vision? (see Section 4.4)

r Unusual skin findings?

r White (ashleaf) spots, common in TSC

r Brown (cafe´ au lait) spots, common in neurofibromatosis 1 (NF1—AD with variable

expressivity)



r Swirls of patchy hypopigmentation (with ID) characteristic of hypomelanosis of Ito

(chromosomal mosaicism/unknown)



r Marbled, swirly patches of skin, characteristic of incontinentia pigmenti (XL dominant)

r Red/purple (port wine) stains (nevus flammeus) seen in Sturge-Weber syndrome

(sporadic)



r Yellow/orange tan nevi seen in sebaceous nevus sequence (sporadic)

r Fatty benign tumors (lipomas)



r Unusual lumps or growths? (neurofibromas in NF1; angiofibromas in TSC)

r Growths under nails? (periungual fibromas are pathognomonic for TSC)

r Cognitive delay (ID) or learning disabilities? (can be seen with NF1, TSC, fragile X

syndrome, maternal teratogens, chromosome anomalies and inborn errors of metabolism

including storage disorders; see Section 4.5)



STROKE



TABLE 4.17



131



(Continued)



r Developmental regression? (can be seen with metabolic disorders particularly storage

disease, mitochondrial disease)



r Problems with walking (gait disturbance)? At what age? (can be seen with several of the

hereditary ataxias, mitochondrial myopathies, and inborn errors of metabolism; see

Section 4.8)

Difficulty with coordination?



r

r Muscle weakness?

r Problems with behavior, thinking, or judgment? (see Sections 4.11 and 4.12)

r Are the parents of the individual with seizures blood relatives—for example, are they cousins?

a Abbreviations: ID = intellectual disability; NF1 = neurofibromatosis 1; TSC = tuberous sclerosis complex;

AD = autosomal dominant; AR = autosomal recessive; XL = X-linked.

Sources: Fernandez and Bird, 2002; Sybert, 2010.



managing the pregnancy of a woman with a seizure disorder and should be discussed

in genetic counseling.



4.10 STROKE

Strokes are the third most common cause of death in the United States. Stroke is an

umbrella term describing several different disease processes, including large vessel

atherosclerosis, small vessel or lacunar disease, and cardioembolism, all of which

result in focal or sometimes global cerebral damage due to disruption of blood flow

to the brain (Francis et al., 2007). An estimated 85% are due to cerebral ischemia and

15% are due to primary intracerebral hemorrhage (Francis et al., 2007).

There are several risk factors for stroke, some of which are modifiable, which

including tobacco use, oxidized LDL, hyperglycemia/diabetes, hypertension, and

periodontal disease. Substance abuse (cocaine and heroin) is another cause. Obesity

is a risk factor for stroke and several of the other risk factors associated with stroke

(such as diabetes and hypertension). The genetic etiology of stroke is likely multigenic

with influence by other risk factors such as tobacco use. Polymorphisms in the

phosphodiesterase 4D gene (PDE4D) seem to increase stroke risk particularly in

association with tobacco use (Munshi and Kaul, 2008).

There are several single-gene disorders of which stroke is part of the multisystem

disorder. Although these are rare, they are important to consider in the evaluation

of person with stroke, particularly if the stroke is below age 55. Fabry disease may

account for 1% of all unexplained (acute cryptogenic) stroke. Although this is an

X-linked disorder, women are affected as well. Single-gene disorders associated

with early stroke are reviewed in Table 4.18. The family history questions in relation to stroke are reviewed in Table 4.19. Stroke can also be seen with congenital

heart disease; rheumatic valve disease; endocarditis; arrhythmias; and after cardiac

surgery, vasculitis, and hypercoagulable states (such as antiphospholipid syndrome,

antithrombin III/protein C deficiencies) (Francis et al., 2007).



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